S158: EFFICACY OF LOW-DOSE TYROSINE KINASE INHIBITOR THERAPY AFTER ACHIEVING MAJOR MOLECULAR RESPONSE IN PERSONS WITH CHRONIC MYELOID LEUKAEMIA
Authors: Zongru LI, Yijing Zhao, Linping Lu, Yong Guo, Ya-Zhen Qin, Qian Jiang
Journal: HemaSphere (2023)

Background: Tyrosine kinase inhibitor (TKI) dose optimization is important to maintain efficacy and mitigate adverse events for chronic myeloid leukaemia (CML) patients. However, the impact of low-dose TKI therapy on outcomes after achieving a major molecular response (MMR) remains undetermined. Aims: To compare the achievement of deeper molecular responses and maintenance of previous responses between low-dose and full-dose TKI therapy after achieving MMR. The factors associated with loss of MMR or MR4 after dose reduction were further explored. Methods: This was a retrospective analysis including adults with chronic or accelerated phase CML who received low-dose or full dose of imatinib, nilotinib or dasatinib after MMR was achieved during the administration of the full-dose TKI. BCR::ABL1 transcript were analyzed using standard real-time quantitative polymerase chain reaction (qPCR) every three months and droplet digital PCR (ddPCR) at the time of dose reduction. The outcomes were compared between low-dose group and full-dose group after landmark analysis and propensity score matching. Multivariate analysis was performed using a Cox’s regression model to identify the factors associated with MMR and MR4 failure-free survival after dose reduction. Results: Consecutive subjects with CML (n=837) in the chronic or accelerated phase who achieved an MMR with initial TKI therapy were analysed; 271 subjects received low-dose TKI therapy at a median of 31 months (IQR, 11–58 months) after achieving a MMR, of whom 230 (85%) were on imatinib, 34 (12%) on nilotinib and 7 (3%) on dasatinib. Subjects in the low-dose group were older (P<0.001), had a higher proportion of accelerated phase at diagnosis (P=0.002), a shorter interval from the start of TKI therapy to achieving a MMR (P<0.001) and a longer duration of follow-up (P<0.001). Landmark analysis and propensity score matching indicated that low-dose TKI therapy had no impact on the 6-year cumulative incidence of MR4 (75% [59, 91%] versus 66% [57, 76%]; P = 0.489), MMR failure-free survival rates (98% [96, 100%] versus 95% [91, 99%]; P = 0.351), MR4 failure-free survival rates (92% [87, 97%] versus 93% [87, 99%]; P = 0.815), progression-free survival (100% versus 99% [98, 100]; P = 0.311) or survival (100% versus 99% [97, 100]; P = 0.236) compared with full-dose TKI therapy, but a lower cumulative incidence of MR4.5 (43%, [31, 56%]) versus 61%, [53, 70%]; P = 0.029) was observed. In 271 subjects receiving low-dose TKI therapy, the MMR and MR4 failure-free survival rates at 6 years were 95% (95% CI: 93, 98%) and 89% (84, 94%), respectively. Multivariate analyses showed age ≥60 years (HR, 3.6; 95% CI [1.1, 11.1]; P=0.029) and BCR::ABL1IS >0.0078% detected by qPCR (4.4 [1.4, 13.9]; P=0.012) at the time of dose reduction were associated with reduced MMR failure-free survival. In 237 subjects with data of ddPCR, age ≥60 years (HR, 4.8 [1.3, 17.0]; P=0.016) and BCR::ABL1IS >0.0032% detected by ddPCR (10.8 [1.4, 85.7]; P=0.025) were associated with reduced MMR failure-free survival. BCR::ABL1IS >0.0048% detected by qPCR (HR, 2.3 [1.0, 5.3]; P = 0.049) or BCR::ABL1IS >0.0029% detected by ddPCR was associated with reduced MR4 failure-free survival. Summary/Conclusion: Post-MMR low-dose TKI therapy had comparable outcomes with full-dose therapy in CML patients. Older age and not achieving MR4 before dose reduction had a higher likelihood of MMR loss.Figure 1 (A) Cumulative incidence of MR4, (B) cumulative incidence of MR4.5, (C) MMR failure-free survival and (D) MR4 failure-free survival between full-dose group and low-dose group after landmark analysis and propensity score matching analysis. Keywords: Chronic myeloid leukemia, Tyrosine kinase inhibitor, Droplet Digital PCR (ddPCR)